Isocitrate dehydrogenase mutations in myeloid malignancies

Abstract

Alterations to genes involved in cellular metabolism and epigenetic regulation are implicated in the pathogenesis of myeloid malignancies. Recurring mutations in isocitrate dehydrogenase (IDH) genes are detected in approximately 20% of adult patients with acute myeloid leukemia (AML) and 5% of adults with myelodysplastic syndromes (MDS). IDH proteins are homodimeric enzymes involved in diverse cellular processes, including adaptation to hypoxia, histone demethylation and DNA modification. The IDH2 protein is localized in the mitochondria and is a critical component of the tricarboxylic acid (also called the ‘citric acid' or Krebs) cycle. Both IDH2 and IDH1 (localized in the cytoplasm) proteins catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG). Mutant IDH enzymes have neomorphic activity and catalyze reduction of α-KG to the (R) enantiomer of 2-hydroxyglutarate, which is associated with DNA and histone hypermethylation, altered gene expression and blocked differentiation of hematopoietic progenitor cells. The prognostic significance of mutant IDH (mIDH) is controversial but appears to be influenced by co-mutational status and the specific location of the mutation (IDH1-R132, IDH2-R140, IDH2-R172). Treatments specifically or indirectly targeted to mIDH are currently under clinical investigation; these therapies have been generally well tolerated and, when used as single agents, have shown promise for inducing responses in some mIDH patients when used as first-line treatment or in relapsed or refractory AML or MDS. Use of mIDH inhibitors in combination with drugs with non-overlapping mechanisms of action is especially promising, as such regimens may address the clonal heterogeneity and the multifactorial pathogenic processes involved in mIDH myeloid malignancies. Advances in mutational analysis have made testing more rapid and convenient, and less expensive; such testing should become part of routine diagnostic workup and repeated at relapse to identify patients who may benefit from treatments that target mIDH.

Metabolic regulation of hematopoietic and leukemic stem/progenitor cells under homeostatic and stress conditions

“…d-2HG also binds to and competitively inhibits the JHDM α-KG binding site [61]. Consequently, cells harboring mutant IDH show decreased JHDM activity and abnormal patterns of histone methylation [62], outcomes associated with a block in HSC differentiation. Mutant IDH activity also affects DNA methylation.…”

Does mIDH Inhibitors is a Promising Therapy?

“…MIDH1/2 is among the most common mutations in AML. IDH1 mutations are less common than IDH2 mutations in AML [7]. Mutations in genes encoding IDH1 and IDH2 gene isoforms occur in 6-16% and 8-19% of AML cases, respectively [3] (~20% of patients have combined mutation) [7].…”

“…The IDHs are tricycle carboxylic acid cycle enzymes which convert isocitrate to α-KG via oxidative decarboxylation, producing NADPH (IDH1 and 2) and NADH (IDH3) [3]. IDH proteins are involved in diverse cellular processes including adaptation to hypoxia, histone demethylation and DNA modification [4]. Mutations have only been identified in IDH1 and IDH2 gene [3].…”

Recent Progress in the Understanding of Angioimmunoblastic T-cell Lymphoma

“…In AITL, IDH mutations are almost exclusively present at p.R172 IDH2, 13,30 whereas IDH1 mutations are found in myeloid malignancies. 38 The biased distribution of IDH mutations may be explained by the different expression profiles of IDH1 and IDH2. IDH1 mRNA is expressed only in myeloid cells, whereas IDH2 mRNA is expressed in both myeloid and lymphoid cells in mice.…”

“…The IDH mutants lead to the abnormal production of (R)-2-hydroxyglutarate (R-2-HG), known as an oncometabolite. 38,40 R-2-HG inhibits α-KG-dependent TET proteins and Jumonji family histone demethylases, resulting in epigenetic alterations in both DNA and histone proteins.…”